The purpose of this application is to study the regulation of the activity of the enzyme ornithine decarboxylase (ODC), thought to catalyze the rate-limiting reaction of polyamine biosynthesis, and to measure polyamine content in the liver and kidney of experimental and genetically diabetic animals. We have found that hepatic and renal ODC activity is elevated in the streptozotocin-induced diabetic rat and that treatment with insulin can restore the hepatic enzyme activity to non-diabetic levels. This finding suggest that polyamines are increased in a catabolic state, and might be suppressed by insulin, normally thought to be a growth promoting hormone. To determine the mechanism involved in the increased ODC activity of streptozotocin-induced diabetes, we plan to study both the whole animal and the perfused liver and kidney of diabetic rats. First, we will study the time course of the increases of the renal and hepatic enzymes. Our preliminary studies suggest the renal enzyme increase occurs earlier than that of the hepatic enzyme. We will determine whether ODC activity in other organs is also elevated. We will correlate the severity of diabetes with the increases of enzyme activity, and will study the effects of correcting specific factors known to be abnormal in the diabetic state. These factors include prevention of ketosis, removal of the pituitary and adrenal glands, reduction of elevated glucagon levels by somatostatin and prevention of prostaglandin synthesis with indomethacin. We plan to determine the possible role for amino acides, cyclic nucleotides, protein synthesis, enzyme degradation, and possible inhibitors of ODC activity in the mechanism of the enzyme elevation. We will study the pancreatectomized rat and the genetically diabetic Chinese hamster to determine whether these diabetic models have similar increases of ODC activity. These results should indicate the effect of diabetes in general on this enzyme activity. Finally, we will correlate changes in hepatic and renal ODC activity of diabetic rats with tissue levels of polyamines.